The invention relates to compositions for controlling ectoparasites. Specifically, the invention provides parasitical pyrethroid- and pyrethrin-containing formulations comprising solvent systems containing glycol ethers and/or terpenes.
Pyrethrins are natural compounds extracted from tropical strains of chrysanthemum flowers (Pyrethrum cinerariaefolium). Pyrethroids are synthetic analogs of pyrethrins. Both pyrethrins and pyrethroids have been used as insecticides for controlling ectoparasites (e.g., fleas, flies and ticks) infestations on animals as described e.g., U.S. Pat. No. 4,020,181. A preferred pyrethroid for this purpose is permethrin.
For purpose of administration, the pyrethroid or pyrethrin typically is formulated in a liquid carrier and then applied topically to an animal in need of relief from fleas or other ectoparasites. Desirable carrier substances are solvents that can be mixed with the active agent to provide formulations that can be poured onto an animal. Carriers substances for pyrethroids and pyrethrins have included, for example, aromatic petroleum products such as xylene and toluene, cyclohexamine, alcohols, corn oil, eucalyptus oil and alkyl glycol ethers. While most prior art pyrethroid-containing insecticidal formulations contain only up to 50% by weight of pyrethroid, U.S. Pat. No. 5,236,954 discloses pyrethroid formulations, in particular permethrin formulations, containing permethrin concentrations greater than 50% by using an alkyl glycol ether such as diethylene glycol monomethyl ether. An insecticidal composition having such a high concentration of active ingredient allows for small, easily applied and yet effective doses.
Concentrations of more than 50% by weight active ingredients make topical application more convenient and more aesthetically acceptable. The higher the concentration, the smaller the dose for effective ectoparasite control. A small dose can be applied to a relatively small region of the skin, thus preventing the host from being covered with solvent. This formula and method of application is particularly useful for treating domestic companion animals such as dogs because the animal will not drip solvent or feel sticky when petting occurs immediately after application. Such small doses can be applied without the treated animal being made aware thus easing administration. Although the composition is applied as one or more small doses to a localized region on the animal, the pyrethroid translocates to effectively control ectoparasite infestation over relatively all of the animal. Formulations containing more than 50% by weight of a pyrethroid thus obtain many advantages not present in formulations having a maximum concentration of only up to 50% by weight of the total formulation.
With a larger concentration of active ingredient, such as for example a 65% or greater solution of permethrin, there is not a large amount of solvent present in the formulation, and it has been discovered that pyrethroids and pyrethrins can crystallize out of solution at lower temperatures, e.g., below about 20xc2x0 C. This is problematic, as it means that the concentration of the pyrethroid or pyrethrin in solution and available for administration to the animal is lessened. Accordingly, there is a need for a solvent system that prevents or minimizes the crystallization of pyrethroids or pyrethrins at lower temperatures.
There is also a need to develop formulations that have a longer period of efficacy than is available from products currently on the market. Products that are efficacious for longer periods of time obviously are desirable as they are more cost effective and will require fewer applications over time to provide effective protection.
The present invention fulfills this need by providing materials and methods for controlling ectoparasite infestations.
One aspect of the invention provides a parasiticidal composition for topical application to an animal that comprises a pyrethroid or a pyrethrin and a carrier, wherein said carrier comprises a terpene, such as d-limonene. In another embodiment of the invention, the carrier also comprises an alkyl glycol ether. Preferred alkyl glycol ethers include propylene glycol monomethyl ether, dipropylene glycol monomethyl ether, and/or diethylene glycol monomethyl ether. Particularly preferred compositions contain a pyrethroid or pyrethrin in an amount greater than 50% by weight of the total composition. Even more preferred are compositions containing a pyrethroid or pyrethrin in an amount at least about 65% by weight of the total composition. Preferably the pyrethroid is permethrin.
All references cited herein are hereby incorporated in their entirety by reference.
The invention provides compositions for controlling ectoparasites that can be found on animals, in particular domestic animals including dogs and cats, but also horses, as well as on food-producing animals such as cattle, sheep and swine. The compositions can be used to treat ectoparasites including fleas, ticks, mange, mites, mosquitoes, nuisance and biting flies, lice, anthropod vectors of disease, as well as internal parasites, e.g., heartworms, hookworms and helmiths.
The compositions of the invention comprise a pyrethroid or a pyrethrin and a carrier comprising a terpene or terpene derivative or a combination of a terpene or terpene derivative and another carrier such as an alkyl glycol ether. Surprisingly, it has been found that when a terpene, such as d-limonene (CAS #5989-27-5), is used as the carrier, crystallization can be minimized and/or avoided. In a preferred embodiment, the carrier comprises a combination of a terpene and propylene glycol monomethyl ether, or a combination of a terpene and dipropylene glycol monomethyl ether (CAS #107-98-2). Preferably the composition comprises from about 30% to about 70% by weight of the terpene or the terpene-alkyl glycol ether combination.
Pyrethroids that can be used to practice the invention include permethrin, phenothrin, acrinathrin, allethrin, bioallethrin, bifenthrin, bioresmethrin, cycloprothrin, cypermethrin, cyhalothrin, lambda cyhalothrin, cyfluthrin, cyphenothrin, tralomethrin, tralocythrin, deltamethrin, empenthrin, fenpropathrin, kadethrin, prallethrin, pyrethrins, resmethrin, sluvalinate, tefluthrin, tetramethrin, transfluthrin, fluvinate, flumethrin and fenvalerate. The most preferred pyrethroid for use in this invention is permethrin (CAS #52645-53-1). Permethrin has a molecular weight of 391.28 grams/mole and technical permethrin comprises from about 25 to 80% cis isomer and from about 20 to 75% trans isomer by weight. In the insecticidal composition of the invention, technical permethrin is suitable and it preferably has a minimum amount of the trans isomer of about 45% by weight and a minimum amount of cis isomer of about 35% by weight.
The ectoparasiticide compositions according to the invention, the concentration of permethrin or other pyrethroid typically is from about 30 about 95% by weight, with preferred level being at least about 45%, even more preferred from 50-75% (by weight). The remaining portion of the composition is the carrier substance.
In addition to d-limonene, other terpenes suitable for use in the claimed invention include (xcex1-pinene, xcex2-pinene, xcex2-myrcene and terpinolene. In addition, terpene derivatives, or terpenoids, may also be used as the carrier or as one component of the carrier. As used herein, the terms xe2x80x9cterpene derivativexe2x80x9d or xe2x80x9cterpenoidxe2x80x9d include terpene alcohols such as geraniol, terpineol and linalool, terpene aldehydes such as citronellal, and terpene ketones such as pulegone, all of which are suitable for use as the carrier or as one component of the carrier in the compounds of the claimed invention.
The terpene, or the terpene alcohol, aldehyde or ketone, can be used as the sole liquid carrier in the compositions of this invention. Alternatively, the carrier can comprise a combination of the terpene or terpene derivative and another carrier, such as hexylene glycol or an alkyl glycol ether. Preferred alkyl glycol ethers include propylene glycol monomethyl ether, dipropylene glycol monomethyl either and diethylene glycol methyl ether. If a mixture of terpene or terpene derivative and alkyl glycol ether is used, the mixture desirable contains at least 10% by weight of the terpene component. Preferably, the ratio of terpene to alkyl glycol ether is from about 3:1 to about 1:3. More preferably, the ratio of terpene to alkyl glycol ether is from about 2:1 to about 1:2. Other conventional carriers can also be used in combination with the terpene or terpene derivative.
The compositions of the present invention are effective against ectoparasites while remaining non-irritating and non-toxic to the host. Inasmuch as the compositions can be formulated with a high concentration of active ingredient they can be easily applied in small yet effective doses. A particularly effective method of application consists of applying the composition to one or more localized regions on the host, such as by applying a small spot of the composition on an animal at the region between its shoulder blades. Larger animals can be treated with a second small spot of the composition at the rump region. It is believed that the pyrethroid component translocates within a relatively short period of time to effectively cover the entire surface of the host""s body. No special expertise is required to apply the treatment so animal owners may do so without the assistance of a health care professional and without special equipment.
Other inert ingredients can be added to the present composition, as desired. Such ingredients include spreading agents, synergists, attractants, repellents, adhesion promoters, surface active agents, stabilizers, skin conditioners, perfumes, odor masking agents, taste deterrants, coat sheeners and coloring agents. Additional active ingredients, such as other insecticides and insect growth regulators can also be included in the composition of the present invention.
Suitable spreading agents are liquids that distribute themselves particularly readily on the skin. Isopropyl myristate is commonly used spreading agent. The desirable properties of spreading agents, sometimes referred to as spreading oils, are generally well known to those skilled in the art. Attractants include pheromones such as 2,6-dichlorophenol. Repellents include citronellol, diethyl toluimide, dimethyl phthalate, and the like.
Of the other inert ingredients that can be utilized with the present invention there are adhesion promoters. Adhesion promoters include carboxymethyl-cellulose, methylcellulose and other cellulose derivatives and starch derivatives, polyacrylates, alginates, gelatin, gum arabic, polyvinylpyrrolidone, polyvinyl alcohol, copolymers of methyl vinyl ether and maleic anhydride, polyethylene glycols, paraffins, oils, waxes and hydrogenated castor oil, colloidal silicic acid or mixtures of these substances.
The compositions of the present invention do not normally contain surface active agents, but these may be included if desired. Surface active agents (comprising emulsifiers and wetting agents) include (i) anionic surface active agents, such as sodium lauryl sulfate, fatty alcohol ether-sulfates and monoethanolamine salts of mono-dialkylpolyglycol ether orthophosphoric acid esters, (ii) cationic surface active agents, such as cetyltrimethyl-ammonium chloride, (iii) amphophilic surface active agents, such as di-sodium-N-lauryl-amino-diproprionate or lecithin, and (iv) non-ionic surface active agents, for example, polyoxyethylated castor oil, polyoxyethylated sorbitane monoleate, sorbitan monostearate, ethyl alcohol, glycerol monostearate, polyoxyethylene stearate and alkylphenol polyglycol ethers.
For preventing chemical degradation that occurs in the case of some active compounds, stabilizers may also be used and include, for example, antioxidants such as tocopherols, butyl-hydroxyanisole, butylhydroxytoluene and carbodiimides, e.g., 2,2-6,6-tetraisopropyldiphenylcarbodiimide), and scavengers such as epichlorhydrin. Coloring agents include conventional dyes that are soluble in the carrier of the present invention, such as Sudan Red or Oil Golden Yellow.
In order to prepare the insecticidal composition of the present invention, a pyrethroid is heated to 65-80xc2x0 C. until any crystals present are liquefied. The liquid is then mixed until uniform. A liquid carrier solvent is placed into a separate unheated vessel. The permethrin is then added to the vessel. The permethrin and carrier solvent are then mixed to uniformity. Additives, such as those listed above (e.g., skin conditioners, perfumes, coat sheeners, and spreading agents), may also be included in the vessel and mixed into the formulation.
In the preferred embodiment of this invention, permethrin is heated to about 65xc2x0 C. A 2:1 to 1:2 mixture of d-limonene and propylene glycol monomethyl ether is placed in a clean tank and the permethrin added and mixed until uniform. After the permethrin has been formulated into this simple liquid mixture, the mixture may serve as a starting point for the formulation of topical preparations in other physical states. For instance, gelling agents may be added to create topical preparations in the form of gels and sols. Gases may be added to create topical preparations that can be delivered as aerosols. Other formulating agents may be added to the liquid mixture to create ointments and pastes.
The insecticidal composition of the present invention is suitable for use on most mammals including humans, horses, cattle, giraffes and domesticated companion animals such as dogs. Because it is so non-toxic, it may be used on young animals, e.g., 3 weeks of age, as well as adult animals. It is also effective against a variety of parasites including ticks, fleas, flies, keds, and mites.
The composition according to the present invention is particularly useful for horses and other large mammals because the doses required are much smaller as compared to the pyrethroid compositions of 50% by weight or lesser concentrations. The insecticidal composition of this invention is useful for the control of arthropods, insects and acarine ectoparasites such as fleas, ticks, flies, keds, and mites. Its most preferred use is for the control of ticks and fleas on dogs.
The composition may be applied to the host animal by any conventional method for the localized application of compositions, for example by dropping a small volume of liquid composition on the mammal""s body. One advantage of the use of a highly concentrated composition is that only a small volume is necessary. The composition applied in this manner appears to exhibit migration, wherein the pyrethroid component is translocated to other regions on the animal body. This migration or spreading effect enables administration of the pyrethroid to relatively all of the animal body surface for ectoparasitic control.
Formulations with pyrethroid concentrations in excess of 50% by weight can be packaged in a single dose package. For example, a single 1 cubic centimeter (cc) dose of a liquid formulation comprised of permethrin and solvent ethanol can be packaged in a collapsible 1 cc tube. Because the formulation avoids the use of strong organic solvents like xylene, cyclohexanone, and toluene, there is greater choice of tube material. Single dose containers make storage and disposal more convenient for animal owners. Multiple dose liquid formulations can be packaged in containers of more than 1 cc capacity. The high concentration composition also decreases container size requirements for multiple dose containers as well as the container size requirements for single dose containers for larger animals. A package assembly of the type described in U.S. Pat. No. 5,344,018 can conveniently be used.
Since the composition has a high concentration of pyrethroid, this small application of a spot or line on the animal will effectively control insect and arachnid parasite infestations on mammals from within three to twenty four hours post administration and for up to four weeks post administration. This method is non-toxic and the concentrated composition does not irritate the animals skin. While a necessary amount of the composition of the present invention needed to be applied for effective insecticidal activity depends upon the size of the animal and the precise concentration and delivery capabilities of the particular composition, a 1 cubic centimeter (cc) volume of the preferred liquid composition has been found to be effective on dogs weighing less than 15 kg. A 1 to 2 milliliter volume of the preferred 65% by weight permethrin delivers 65-130 mg permethrin. On dogs larger than 15 kg, it has been found to be effective to apply 1 cc of 65% by weight permethrin composition between the shoulder blades in conjunction with another 1 mL at the tailhead. In a preferred embodiment, for every kilogram of the host body weight, about 33 or more milligrams of the composition should be applied.
The present invention is more particularly described in the following examples which are intended as illustrative only since numerous modifications and variations therein will be apparent to those skilled in the art.